Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 27, 2026.

Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy

Lovro Žiberna, Dunja Šamec, Andrei Mocan and 5 more

International Journal of Molecular Sciences · 2017 · Review · CC BY

doi:10.3390/ijms18030643

Abstract

Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5′ adenosine monophosphate-activated protein kinase, extracellular signal–regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Cancer is known as one of the major global health problems throughout the world, mainly due to changes in lifestyle, as well as unhealthy diets and environmental pollution. Currently, the global map of cancer prevalence is rapidly changing. Referring to Western societies, there has been a decrease in most cancer-related mortality. Meanwhile incidence and mortality continue to rise quickly in developing or undeveloped countries.

Nowadays, cancer has been considered as an important cause of death and it is estimated that it will be more than 18 billion in the next five years. Despite the substantial progress made in diagnosis and treatment, current therapeutic protocols, such as radiotherapy, phototherapy, chemotherapy, immunotherapy, as well as surgical protocols, are limited and still associated with low outcome, and high morbidity and mortality rate, suggesting crucial needs for finding new effective therapeutic agents.

The term “chemoprevention” refers to use of pharmacological agents, nutraceutical, as well as bioactive natural products, to prevent or delay cancer development. Recently, much attention has been paid to the clinical usage of natural products as anticancer agents to prevent cancer or delay its development.

Epidemiological evidence shows that there is a reverse correlation between high intake of vegetables and fruits and developing non-communicable disease, such as certain types of cancer, stroke, and neurodegenerative diseases. This statement is particularly ascribed to the presence of a variety of non-nutritive phytochemical agents from plant-based foods. At the same time, a compelling trend and one of the current dilemmas in natural products research is what is more beneficial: the plant extract/herbal product or its active phytoconstituents? The researchers that are in favor of the “whole” argue that the therapeutic efficacy of an extract is the outcome of synergistic or additive effects of its various bioactive components, while those who prefer purified compounds contend that, unlike isolated compounds, several phytochemicals present as a mixture in a natural source are not bioavailable, or have limited bioavailability and, therefore, are less useful. Both arguments present valid hypotheses and, despite the fact that a significant amount of investigation has been carried out in the field, results do not proclaim a winning side.

When considering the influence of dietary patterns, many efforts have been carried out to evaluate the association between certain dietary models and their health claims as well as the influence of particular single components from the wide range of other nutrients or non-nutrients. Nonetheless, it is worth mentioning that, among various dietary patterns, a traditional Mediterranean diet has been revealed as one of the healthiest choices and this claim is being ascribed to the consumption of copious amounts of olive oil. Despite being less investigated than phenolic compounds, current studies on olive oil triterpenoids, such as oleanolic acid, have revealed a marked potential in altering different cell signaling pathways and, thus, reveal significant potential in cancer prevention and therapy.

This review presents the chemistry, sources, and bioavailability, as well as the anticancer effects of oleanolic acid, with a particular emphasis on molecular mechanisms of action.

2. Chemistry and Biosynthesis

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid) is one of the most common pentacyclic triterpenoid compounds mainly found in different herbal sources. It is a non-volatile light yellow compound soluble in 1-butanol and ethyl acetate and less soluble in ethanol, 2-propanol, methanol, acetone, and water, where solubility increases with an increase in temperature. Triterpenoid compounds possess great pharmacological potential, and their biosynthetic pathways in plants have been thoroughly studied. As reviewed by Pollier and Goossens, oleanolic acid biosynthesis goes from the primary sterol metabolism precursor 2,3-oxidosqualene (synthesized in the mevalonate pathway), which is cyclized to β-amyrin by the enzyme β-amyrin synthase. Further, β-amyrin and erythrodiol undergo three consecutive oxidation steps at the C-28 position by the cytochrome P450 (CYP) enzyme to produce oleanolic acid. Oleanolic acid in plants occurs both in its free form, and also as a triterpenoid saponin aglycone linked to one or more sugar moieties. In its free form, it is found in plants cuticular waxes, where it is involved in plant biotic and abiotic stress responses.

In plants and plant-based foods, oleanolic acid is often found together with isomer ursolic acid, from which it differs by the sites of the methyl group on the E loop (Figure 1). Both isomers have similar pharmacological properties, although they can differ in the intensity of biological activity due to the difference in the position of the methyl groups, which influences their potency and consequently bioactivity of compounds. Oleanolic acid is a registered drug for treating liver diseases in China. In the last 20 years, numerous investigations have been centered on the chemical modifications of oleanolic acid in order to make it more effective and/or develop water soluble derivatives, which resulted in hundreds of new compounds with diverse biological activities. Among the most studied compounds, bardoxolone methyl has been evaluated in several clinical trials for diabetes mellitus, chronic kidney disease, and various types of cancer.

3. Sources and Bioavailability

Oleanolic acid is found in more than 1600 plant species. Aerial parts of higher plants are covered with a hydrophobic layer called the cuticule, which forms a protective coating important for plant survival in its environment. The cuticle contains two structural ingredients, including a polymeric matrix called cutin, and epicuticular wax which can be distinguished in intracuticular and epicuticular layers. Numerous research reported that triterpenoids in plants are found concentrated in the intracuticular wax compartment (reviewed in). Therefore, oleanolic acid content is much higher in fruit “skin” or “peel” (non-botanical terms which include cuticle and multiple cell types) in comparison with the pulp (Table 1). In general, fruits which are consumed with the skin, including dried fruits, can be better dietary sources of oleanolic acid. The most important sources of oleanolic acid in human diet are olives (Olea europaea L.), from which the compound derives its name, and their products, such as olive oil. It is estimated that in the Mediterranean diet, containing olives and olive oils, total daily intake of oleanolic acid is around 25 mg. In addition to olives, other foods common in the Mediterranean diet, such as various legumes, contain oleanolic acid in the range of 0.251–2.591 µg/g fresh weight (fw). High amounts of oleanolic acid are also present in edible parts of jujube (Ziziphus jujube Mill.), a commonly consumed fruit in Southern Asia and China.

Although triterpenes in free form are found in cuticular waxes of edible plants, roots of medicinal plants, such as ginseng (Panex sp.) and wild sage (Lantana camara L.), are also high in oleanolic acid. Hawthorn berries (Crataegus sp.), and fruits of Chinese privet (Ligustrum lucidum W.T. Aiton) and Chinese quince (Chaenomeles sinensis (Thouin) Koehne) stand out among other plants used in traditional medicine as a good source of oleanolic acid. Additionally, numerous other medicinal and aromatic plants contain oleanolic acid. Large scale studies have shown its presence in 88 taxa of Lamiaceae family. Comparative analysis of 38 commercial herbal extracts showed the presence of oleanolic acid in extracts of Aesculus hyppocastanum L., Crataegus monogyna L., Harpagophytum procumbens DC, Lagerstroemia speciosa L., Ortosiphon stamineus L., Punica granatum L., Styrax benzoin Dryand., Vaccinium myrtillus L. and Vitis vinifera L.. Oleanolic acid is also detected in propolis and numerous plant-based products, including spices, vegetable oil, and snack products, containing dried whole fruits.

Biological effects of food components do not depend solely on their amount in certain food, but rather on their bioavailability. Bioavailability is the proportion of a compound that enters the systemic circulation when introduced into the body. Experimental and clinical studies reported the presence of oleanolic acid in blood several hours after intake in its intact form, but oral bioavailability was low due to low aqueous solubility and intensive metabolism by cytochrome P450 isoenzymes (CYP). Jeong et al. reported that the bioavailability of oleanolic acid after oral administration was only 0.7% in rats. Therefore, in recent years much scientific efforts have been put on creation of complexes and formulations that could increase oleanolic acid bioavailability through increased solubility and permeability. On the other hand, bioavailability does not depend only on physical and chemical properties of a compound, but on the fact that other micro-and macronutrients present in consumed foods affect the bioavailability and metabolism of the targeted compound. In this area, studies on oleanolic acid are still insufficient.

4.1. Oleanolic Acid Inhibited Tumor Initiation and Development

The anticancer effects of oleanolic acid have been evaluated in many cancer types, including liver cancer, lung cancer, breast cancer, colon cancer, bladder cancer, prostate cancer, pancreatic cancer, gastric cancer, gallbladder cancer, osteosarcoma, hematological malignancies, e.g., leukemia, as well as in central nervous system cancers, such as malignant glioma.

Anticancer activity of oleanolic acid was initially described by inhibition of the tumor promotion of mouse skin cancer cells under in vivo conditions. In this model, oleanolic acid inhibited chemically-induced carcinogenesis through inhibition of irregular gene expression of several studied genes in mouse skin cancer cells. In another study, chronic oral administration of oleanolic acid (five times a week for four weeks) decreased colon carcinogenesis in rats, showing that oleanolic acid can inhibit tumor initiation.

Oleanolic acid dose-dependently suppressed tumor promotion and caused cell cycle arrest at G0/G1 phase in prostate cancer cells, at G0/G1 phase in gallbladder cancer cells, at S phase and/or G2/M phase in pancreatic cancer cells, at subG1 phase in hepatocellular carcinoma cells, and at G2/M phase via inhibition of cyclin B1/cdc2 mediated by p21 in hepatocellular carcinoma cells. Oleanolic acid treatment of lung cancer cells can also cause cell cycle arrest by modulating miR-122/cyclin G1/MEF2D axis. Modification of the miR-122 activity is a novel anticancer strategy, since this microRNA suppresses cancer cell survival, proliferation, and invasion.

Oleanolic acid and its derivatives act as inhibitors of the phosphatidylinositide 3-kinase/protein kinase B/mammalian target of rapamycin/nuclear factor-κB (PI3K/Akt/mTOR/NF-κB) signaling pathway in a dose-dependent fashion. Another study showed that oleanolic acid inhibited Akt/mTOR/S6K signaling pathway. Oleanolic acid reduced the phosphorylation of PI3K and Akt, which are the upstream molecules of mTOR pathway, whereas there were no significant changes in the expression levels of total PI3K or Akt. These effects are probably mediated by reactive oxygen species (ROS) because treatment of cells with antioxidants, such as N-acetylcysteine, reversed the inhibitory activity of oleanolic acid. In addition, over-expression of Akt also reversed the effects of oleanolic acid. Importantly, oleanolic acid is also an inhibitor of extracellular signal–regulated kinase/c-Jun N-terminal kinase/mitogen-activated protein kinase (ERK/JNK/p38 MAPK) signaling pathway mediated by the activation of the 5′ adenosine monophosphate-activated protein kinase (AMPK) signaling pathway that consequently activates downstream signaling leading to the mTOR inhibition and activation of autophagy. A significant decrease in p-p38α/p38α ratio and in the levels of p-JNK1 and pERK1/2 together with the increased phosphorylation of AMPK were reported in oleanolic acid-treated cancer cells. Oleanolic acid via an AMPK activation-dependent manner also induced metabolic alterations in cancer cells, such as suppressed lipogenesis, protein synthesis, and aerobic glycolysis, thus having tumor suppressor activity. Moreover, it has been demonstrated that ERK activation plays a pivotal role in cancer cells resistant to oleanolic acid’s pro-apoptotic activity. Therefore, pharmacological ERK suppression increased anticancer activity by sensitizing cancer cells to oleanolic acid.

From the tumor cell proliferation perspective, oleanolic acid acted as an inhibitor of transforming growth factor-β (TGF-β) by binding to its receptors. Cancer cells respond to excessive production of TGF-β in a pro-tumorigenic manner. In addition, the isomer of oleanolic acid, ursolic acid, inhibited TGF-β/Smad signaling pathways with the antagonistic activity in the low micromolar range (IC50 = 6.9 µM). Moreover, oleanolic acid also inhibited topoisomerase I and IIα proteins, which are key enzymes involved in tumor cell proliferation, by relaxing DNA supercoiling inside cells. It has been demonstrated that topoisomerase inhibition activates the NF‑κB pathway. The suppression of Top-I and Top-IIα resulted in the inhibition of the NF‑κB pathway via p‑IκBα and p‑p65‑dependent manner.

Oleanolic acid also induced apoptosis through a mitochondrial-dependent pathway by altering mitochondrial membrane potential, releasing caspase activators, such as cytochrome c, into the cytoplasm, leading to the fragmentation of nuclear DNA in human cancer cells. The effects can be mediated by the alteration of expression levels of the pro- and anti-apoptotic Bcl-2 families, as evidenced by the decreased expression of anti-apoptotic Bcl-2 and the increased expression of proapoptotic Bax.

Although most studies are focused on isolated oleanolic acid and several derivatives, studies on plant extracts containing triterpenes, including oleanolic acid, are also reported. For example, various extracts of Oldenlandia diffusa, member of the Rubiaceae family, have been shown to be effective against a number of cancer models, including breast cancer, small cell lung carcinoma, or leukemia cells. Crataegus pinnatifida, belonging to the Rosaceae family, is another example of a medicinal plant with potential effects against cancer cells. Triterpenoids-enriched fraction demonstrated notable antiproliferative activities against liver and breast carcinoma cells. Ethyl acetate extract from Betula utilis, a member of the Betulaceae family, exerted cytotoxic activity against cancer cell lines, such as breast, head and neck, lung, ovary, colon, and cervical carcinoma cells.

4.2. Oleanolic Acid Induced Apoptosis

Oleanolic acid induced apoptosis of tumor cells in numerous cancer cell lines, including acute myeloid leukemia, liver cancer cells, osteosarcoma cells, non-small cell lung cancer cells (NSCLC), breast cancer cells, gastric cancer cells, pancreatic cancer cells, prostate cancer cells, bladder cancer cells, and colorectal cancer cells.

Oleanolic acid and its derivatives induced both extrinsic and intrinsic apoptosis by multiple signaling pathways. Extrinsic apoptosis was induced in human lung cancer cells by oleanolic acid derivative, methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, via MAPK pathways, leading to caspase-8 activation. Oleanolic acid derivative, SZC015, activated intrinsic apoptosis, as observed by the up-regulation of caspase-3 and caspase-9, poly (ADP-ribose) polymerase (PARP) cleavage, release of cytochrome c, as well as increase in Bax/Bcl-2 expression ratio. Moreover, oleanolic acid and its derivatives also caused autophagy, i.e., formation of autophagic vacuoles, elevated microtubule-associated protein 1 light chain 3α (MAP1LC3A), increased LC3II/LC3I ratio and upregulated the expression of Atg5 and beclin1 in hepatic, breast and gastric cancer cells. Interestingly, oleanolic acid-triggered autophagy was ROS-dependent as shown by elevated cellular ROS levels, and the effect was abolished if ROS levels were reduced. Indeed, increased ROS levels were responsible for the increased anticancer activity in the co-administration of oleanolic acid together with routinely used chemotherapeutic drug (sorafenib) in hepatocellular carcinoma. Mechanistically, oleanolic acid dose- and time-dependently stimulated apoptosis via activation of ROS/apoptosis signal-regulating kinase 1 (ASK1)/p38 MAPK pathway. Oleanolic acid induced the activation of ASK1 mediated by ROS levels which, in turn, phosphorylated p38 MAPK and subsequently activated pro-apoptotic proteins by phosphorylation of Bax, Bim, and Bcl-2.

In a recent study, oleanolic acid modified Warburg-like metabolism, which was induced by high salt-mediated suppression of cytochrome oxidase, caspase cascade as well as the expression of Bax protein. This study suggested that oleanolic acid can cause apoptosis through mitochondrial-related pathways promoting the release of mitochondrial-associated caspases and pro-apoptotic Bax proteins. In addition, oleanolic acid inhibited aerobic glycolysis by inducing pyruvate kinase muscle (PKM)isoforms switch from PKM2 to PKM1 through suppression of phosphorylated mTOR, consequently disrupting Warburg effects in various cancer cells.

4.3. Oleanolic Acid Mediated Control of TRAIL-Induced Signaling

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated signaling is an extensively-studied area of oncology, and has led to developing a sharper understanding of the protein network, which is functionalized to promote apoptosis in cancer cells without affecting non-tumor cells. TRAIL transduces the signals intracellularly by activating death receptors (DR4 and DR5) situated on the surface of neoplastic cells. Structural interaction of TRAIL with its receptors induces clustering of the receptors into high-molecular-weight nano-complexes that facilitates the development of the death-inducing signaling complex (DISC). DISC formation is necessary to activate caspase-8. Caspase-8 proteolytically processes a downstream effector caspase-3. Once caspase-8 is activated, its downstream effector is channelized through receptors and termed as an extrinsic pathway. However, intrinsic pathway is functionalized through entry of truncated Bid (tBid) into mitochondrion. Importantly, tBid promotes the mitochondrial release of cytochrome c. Cytochrome c interacts with pro-caspase-9 and apoptotic protease activating factor to generate the apoptosome. Functionally, active caspase-9 further activates caspase-3 in cancer cells leading to apoptosis activation.

TRAIL-induced apoptosis is frequently impaired in cancer cells mainly because of downregulation of DR4 and DR5, inactivation of pro-apoptotic proteins, and overexpression of anti-apoptotic proteins. Different synthetic and natural products have been reported to induce apoptosis in TRAIL-resistant cancer cells. In the following sections, we summarize how oleanolic acid modulated this protein network in cancer cells.

A derivative of oleanolic acid, 3-O-acetyloleanolic acid, was found to effectively improve TRAIL-mediated apoptosis in human colon tumor (HCT)-116 cancer cells. Detailed mechanistic insights revealed that 3-O-acetyloleanolic acid upregulated DR5 expression in the treated colon cancer cells. Indeed, also markedly enhanced levels of caspase-8 and caspase-3 were noticed in those cells.

Synthetically-designed cyanoenone of methyl boswellates (CEMB), a triterpenoid compound, was also reported to exert its anticancer effects via upregulation of DR4. Gene silencing strategy confirmed that CEMB-mediated apoptosis was dramatically reduced in DR4-silenced prostate cancer cells.

Another synthetically designed triterpenoid that has entered into clinical trials is methyl-2-cyano-3,12-dioxoolean-1,9-dien-28-oate (CDDO-Me). CDDO-Me transcriptionally upregulated DR5 by an important protein, namely C/EBP homologous protein (CHOP). CHOP binding sites have previously been identified in the promoter region of DR5. Research data showed that CDDO-Me-induced apoptotic effects were significantly impaired in CHOP silenced cancer cells. CDDO-imidazolide potentiated the expression of DR4 and DR5 in acute myeloid leukemia cells, and downregulated decoy receptors (TRAIL-R3/TRAIL-R4).

Overall, accumulating evidence clearly suggests that oleanolic acid plays a significant role in improving TRAIL-mediated cytotoxic activity via upregulation of death receptors, elevation of pro-apoptotic proteins, and inhibition of anti-apoptotic proteins in treated cancer cells.

4.4. Oleanolic Acid Inhibited Angiogenesis, Invasion and Metastasis

Oleanolic acid inhibited invasion of tumor cells, angiogenesis and metastasis in several cancer models. For instance, oleanolic acid reduced the rate of lung metastasis in vivo in osteosarcoma and NSCLC, as well as inhibited the angiogenesis in colorectal cancer.

From an angiogenic perspective, oleanolic acid suppressed the activation of the signal transducer and activator of transcription 3 (STAT3) and sonic hedgehog signaling pathways, which are key pathways in angiogenesis, and downregulated proangiogenic vascular endothelial growth factor A and basic fibroblast growth factor.

Pharmacophore modeling study of oleanolic acid was performed to identify novel analogs of oleanolic acid with the aim to improve the inhibition of human breast cancer cells migration, proliferation, and invasion. This study also discovered that Brk/Paxillin/Rac1 pathway plays an essential role in the antimigratory and anti-invasive effects of oleanolic acid and its derivatives. Twelve semi-synthetic analogues of oleanolic acid were tested from which carbamate derivatives, 3-O-[N-(30-chlorobenzenesulfonyl)-carbamoyl]-oleanolic acid and 3-O-[N-(50-fluorobenzenesulfonyl)-carbamoyl]-oleanolic acid showed strong and selective anticancer activities against breast cancer cells. The authors concluded that the existence of a sulfonyl-carbamoyl moiety with an optimal bulkiness of electron-deficient phenyl ring was predominantly responsible for the increased antineoplastic activity.

4.5. Oleanolic Acid Suppressed Multi-Drug Resistance Proteins

Oleanolic acid has antiproliferative and proapoptotic effects in a time- and dose-dependent manner on various multi-drug resistance cancer cell lines in in vitro conditions associated with a down-regulation of apoptosis antagonistic proteins, including Bcl-2, Bcl-xL, and survivin. Oleanolic acid inhibited the effect of the multi-drug resistance-associated protein 1 (MRP1) and was also cytotoxic to the multi-drug resistant erythroleukemic cells overexpressing permeability glycoprotein (P-gp). Oleanolic acid was able to modulate MRP1 activity without altering its gene expression, but no effects were reported in P-gp activity in a renal cell line expressing constitutively both proteins. Multiple drug resistance is considered to be one of the leading reasons of failure of chemotherapy in cancer patients; therefore, oleanolic acid has potential as a chemotherapeutic agent itself in tumors with high expression of efflux transporters, such as MRP1 or P-gp, or as a co-adjuvant in the chemotherapy of P-gp/MRP1 expressing tumors. However, P-gp and MRPs are also found in non-tumoral tissues. For this reason, it seems to be a prudent approach to use non-toxic inhibitors of efflux transporters, such as oleanolic acid, which is likely to maintain normal physiological function in healthy tissues.

4.6. Oleanolic Acid Exerted Synergistic Activity with Chemotherapeutic Drugs

Combined use of oleanolic acid and 5-fluorouracil synergistically potentiated the cytotoxicity on pancreatic cancer cells as well as acted in pro-apoptotic fashion. In a similar manner, oleanolic acid could be combined with other chemotherapeutic agents.

4.7. Oleanolic Acid Displayed Radiosensitizing Effects

Oleanolic acid increased the radiosensivity of tumor cells by inhibiting the synthesis of cellular glutathione (GSH) with concurrent inhibition of γ-glutamylcysteine synthetase (γ-GCS), a key enzyme in GSH synthesis.

5. Increased Selective Toxicity of Novel Oleanolic Acid Derivatives

Importantly, novel oleanolic acid derivatives have been recently synthesized and tested against various human cancer cell lines, and several of those compounds had cytotoxic activity against cancer cells in the low micromolar range (EC50 = 3–6 µM) and cytotoxicity against non-cancer cells in high micromolar range (EC50 > 120 µM) providing the conditions for selective toxicity. Various oleanolic acid derivatives, including lactams, ketones, oximes, and nitriles, were tested in different cancer cell lines with evidence that lactams and oximes exerted the most cytotoxicity effects. The introduction of acetyl groups at positions C-2 and C-3 and the existence of (2β,3β)-configured centers appears to be necessary for the cytotoxic effects and to obtain the best selectivity between cancer cells and normal mouse fibroblast cells. These results show rationale to employ oleanolic acid and its derivatives as lead compounds in anticancer drug discovery. In addition, novel drug design forms, such as solid inclusion complexes of oleanolic acid with amino-appended β-cyclodextrins, multivesicular liposomes for oleanolic acid, or oleanolic acid-loaded PEGylated polylactic acid, and polylactic-co-glycolic acid nanoparticles, improved oleanolic acid bioavailability and, thus, increased its anticancer potency.

6. Perspectives on Using Oleanolic Acid as an Adjuvant of Cancer Treatment

Natural product chemistry has undergone substantial broadening and many of the phytochemicals have entered various phases of clinical trials. Oleanolic acid has attracted considerable attention because of its cancer inhibitory roles via regulation of different signaling cascades (summarized in Table 2). However, the existing information related to how oleanolic acid modulates different proteins of different intracellular signaling networks is still incompletely studied. We still need to intensely study cell-type specific and context-dependent effects exerted by oleanolic acid on different proteins either to inhibit cancer progression, or to induce apoptosis. Importantly, how oleanolic acid re-balances pro-apoptotic and anti-apoptotic protein stoichiometric ratios needs detailed future research. The most consistent pathway reported involves the induction of autophagy by oleanolic acid via suppressing mTOR through inhibition of the PI3K/AKT and ERK/p38 MAPK signaling pathways and activation of the AMPK signaling pathway. Certain hints have also emerged highlighting how oleanolic acid differentially modulates oncogenic and tumor suppressor miRNAs. Nevertheless, we have to develop a better understanding of the miRNAs which are activated or inhibited in oleanolic acid-treated cancer cells. Different signaling cascades particularly, Wnt, sonic hedgehog, TGF, Notch, and Janus kinase-STAT, have to be comprehensively investigated in different cancers. These aspects will provide a better comprehension regarding to molecular targets underlying anticancer effect of oleanolic acid. Several studies have also documented that plant extracts belonging to different families and containing oleanolic acid are effective against many cancer cell lines. However, up to date no comparisons between the extract and the isolated compounds have been designed in order to determine additive or synergistic effects of the extracts with respect to the individual compounds.

7. Conclusions

Oleanolic acid has the potential to be employed in clinical practice in adjuvant anticancer treatment because: (i) it has direct anticancer activity and can act synergistically with chemotherapeutic drugs; (ii) it inhibits efflux transporters, thereby increasing the intracellular concentration of chemotherapeutic drug; (iii) it exhibits a radiosensitizing effect for irradiation-induced cell death, thereby increasing the efficacy of radiation therapy; and (iv) it has relatively low toxicity and does not have any adverse effects when combined with chemotherapeutic agents. Additionally, anticancer properties of oleanolic acid was in the low micromolar range, which corresponds to the physiologically relevant values obtainable upon oleanolic acid-enriched diet, thereby offering the potential to use oleanolic acid as a vital part of healthy diet. The main limitation of the potential therapeutic use of oleanolic acid is the absence of clinical trials which are necessary to confirm the promising data about its chemoprotective and anticancer effects. In addition, similar to other phenolic compounds, the poor bioavailability limits its potential effects and makes it necessary to find new formulations that increase its bioavailability and effectiveness.

References 118

  1. 1.

    Surh Y.J. Cancer chemoprevention with dietary phytochemicals. Nat. Rev. Cancer. 2003;3:768-780.

    Not in our library10.1038/nrc1189

  2. 2.

    Hussain S.S., Kumar A.P., Ghosh R. Food-based natural products for cancer management: Is the whole greater than the sum of the parts? Semin. Cancer Biol. 2016;40–41:233-246.

    Not in our library10.1016/j.semcancer.2016.06.002

  3. 3.

    Torre L.A., Bray F., Siegel R.L., Ferlay J., Lortet-tieulent J., Jemal A. Global Cancer Statistics, 2012. CA Cancer J. Clin. 2015;65:87-108.

    Not in our library10.3322/caac.21262

  4. 4.

    Bandhavkar S. Cancer stem cells: A metastasizing menace! Cancer Med. 2016;5:649-655.

    Not in our library10.1002/cam4.629

  5. 5.

    Neergheen V.S., Bahorun T., Taylor E.W., Jen L.S., Aruoma O.I. Targeting specific cell signaling transduction pathways by dietary and medicinal phytochemicals in cancer chemoprevention. Toxicology. 2010;278:229-241.

    Not in our library10.1016/j.tox.2009.10.010

  6. 6.

    Bishayee A. Editorial: Current Advances in Cancer Prevention and Treatment by Natural Products. Curr. Pharm. Biotechnol. 2012;13:115-116.

    Not in our library10.2174/138920112798868629

  7. 7.

    Manach C., Hubert J., Llorach R., Scalbert A. The complex links between dietary phytochemicals and human health deciphered by metabolomics. Mol. Nutr. Food Res. 2009;53:1303-1315.

    Not in our library10.1002/mnfr.200800516

  8. 8.

    Bishayee A., Sethi G. Bioactive natural products in cancer prevention and therapy: Progress and promise. Semin. Cancer Biol. 2016;40–41:1-3.

    Not in our library10.1016/j.semcancer.2016.08.006

  9. 9.

    Orlikova B., Legrand N., Panning J., Dicato M., Marc D. Anti-Inflammatory and Anticancer Drugs from Nature. Adv. Nutr. Cancer. 2014;159:123-143.

    Not in our library10.1007/978-3-642-38007-5_8

  10. 10.

    Tuorkey M.J. Cancer Therapy with Phytochemicals: Present and Future Perspectives. Biomed. Environ. Sci. 2015;28:808-819.

    Not in our library10.1016/s0895-3988(15)30111-2

  11. 11.
    Phytochemicals in Cancer Prevention and Therapy: Truth or Dare? · 2010
    No notice
  12. 12.

    Rodriguez-Rodriguez R. Oleanolic Acid and Related Triterpenoids from Olives on Vascular Function: Molecular Mechanisms and Therapeutic Perspectives. Curr. Med. Chem. 2015;22:1414-1425.

    Not in our library10.2174/0929867322666141212122921

  13. 13.

    Shanmugam M.K., Nguyen A.H., Kumar A.P., Tan B.K.H., Sethi G. Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer. Cancer Lett. 2012;320:158-170.

    Not in our library10.1016/j.canlet.2012.02.037

  14. 14.

    Zhang W., Men X., Lei P. Review on anti-tumor effect of triterpene acid compounds. J. Cancer Res. Ther. 2014;10:14-19.

    Not in our library10.4103/0973-1482.139746

  15. 15.

    Parikh N.R., Mandal A., Bhatia D., Siveen K.S., Sethi G., Bishayee A. Oleanane triterpenoids in the prevention and therapy of breast cancer: Current evidence and future perspectives. Phytochem. Rev. 2014;13:793-810.

    Not in our library10.1007/s11101-014-9337-5

  16. 16.

    Shanmugam M.K., Dai X., Kumar A.P., Tan B.K.H., Sethi G., Bishayee A. Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: Preclinical and clinical evidence. Cancer Lett. 2014;346:206-216.

    Not in our library10.1016/j.canlet.2014.01.016

  17. 17.

    Pollier J., Goossens A. Oleanolic acid. Phytochemistry. 2012;77:10-15.

    Not in our library10.1016/j.phytochem.2011.12.022

  18. 18.

    Fan J.-P., Kong T., Zhang L., Tong S., Tian Z.-Y., Duan Y.-H., Zhang X.-H. Solubilities of ursolic acid and oleanolic acid in four solvents from (283.2 to 329.7) K. J. Chem. Eng. Data. 2011;56:2723-2725.

    Not in our library10.1021/je101309a

  19. 19.

    Liu L., Wang X. Solubility of oleanolic acid in various solvents from (288.3 to 328.3) K. J. Chem. Eng. Data. 2007;52:2527-2528.

    Not in our library10.1021/je700312r

  20. 20.

    Liu J. Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol. 1995;49:57-68.

    Not in our library10.1016/0378-8741(95)90032-2

  21. 21.

    Yan S., Huang C., Wu S., Yin M. Oleanolic acid and ursolic acid induce apoptosis in four human liver cancer cell lines. Toxicol. In Vitro. 2010;24:842-848.

    Not in our library10.1016/j.tiv.2009.12.008

  22. 22.

    Senthil S., Chandramohan G., Pugalendi K.V. Isomers (oleanolic and ursolic acids) differ in their protective effect against isoproterenol-induced myocardial ischemia in rats. Int. J. Cardiol. 2007;119:131-133.

    Not in our library10.1016/j.ijcard.2006.07.108

  23. 23.

    Lin C., Wen X., Sun H. Oleanolic acid derivatives for pharmaceutical use: A patent review. Expert. Opin. Ther. Pat. 2016;26:643-655.

    Not in our library10.1080/13543776.2016.1182988

  24. 24.

    Chin M.P., Reisman S.A., Bakris G.L., O’grady M., Linde P.G., McCullough P.A., Packham D., Vaziri N.D., Ward K.W., Warnock D.G. Mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. Am. J. Nephrol. 2014;39:499-508.

    Not in our library10.1159/000362906

  25. 25.
    Fruit cuticular waxes as a source of biologically active triterpenoids · 2012
    No notice
  26. 26.

    Zhang F., Daimaru E., Ohnishi M., Kinoshita M., Tokuji Y. Oleanolic acid and ursolic acid in commercial dried fruits. Food Sci. Technol. Res. 2013;19:113-116.

    Not in our library10.3136/fstr.19.113

  27. 27.

    Perez-Camino M.C., Cert A. Quantitative determination of hydroxyl pentacyclic triterpene acids in vegetable oils. J. Agric. Food Chem. 1999;47:1558-1562.

    Not in our library10.1021/jf980881h

  28. 28.

    Juan M.E., Planas J.M. 25 Effects of Pentacyclic Triterpenes from Olives on Colon Cancer. Bioact. Foods Extr. Cancer Treat. Prev. 2010;403-413.

    Not in our library10.1201/b10330-29

  29. 29.

    Kalogeropoulos N., Chiou A., Ioannou M., Karathanos V.T., Hassapidou M., Andrikopoulos N.K. Nutritional evaluation and bioactive microconstituents (phytosterols, tocopherols, polyphenols, triterpenic acids) in cooked dry legumes usually consumed in the Mediterranean countries. Food Chem. 2010;121:682-690.

    Not in our library10.1016/j.foodchem.2010.01.005

  30. 30.

    Guo S., Duan J., Qian D., Tang Y., Wu D., Su S., Wang H., Zhao Y. Content variations of triterpenic acid, nucleoside, nucleobase, and sugar in jujube (Ziziphusjujuba) fruit during ripening. Food Chem. 2015;167:468-474.

    Not in our library10.1016/j.foodchem.2014.07.013

  31. 31.

    Chan T.W.D., But P.P.H., Cheng S.W., Kwok I.M.Y., Lau F.W., Xu H.X. Differentiation and authentication of Panax ginseng, Panaxquinquefolius, and ginseng products by using HPLC/MS. Anal. Chem. 2000;72:1281-1287.

    Not in our library10.1021/ac990819z

  32. 32.

    Banik R.M., Pandey D.K. Optimizing conditions for oleanolic acid extraction from Lantana camara roots using response surface methodology. Ind. Crops Prod. 2008;27:241-248.

    Not in our library10.1016/j.indcrop.2007.09.004

  33. 33.

    Wang C. Crataeguspinnatifida Bge. (Shanzha, Hawthorn Fruit). Dietary Chinese Herbs. 2015;355-361.

    Not in our library

  34. 34.

    Yim T.K., Wu W.K., Pak W.F., Ko K.M. Hepatoprotective action of an oleanolic acid-enriched extract of Ligustrumlucidum fruits is mediated through an enhancement on hepatic glutathione regeneration capacity in mice. Phyther. Res. 2001;15:589-592.

    Not in our library10.1002/ptr.878

  35. 35.

    Fang X., Wang J., Yu X., Zhang G., Zhao J. Optimization of microwave-assisted extraction followed by RP-HPLC for the simultaneous determination of oleanolic acid and ursolic acid in the fruits of Chaenomelessinensis. J. Sep. Sci. 2010;33:1147-1155.

    Not in our library10.1002/jssc.200900726

  36. 36.

    Janicsák G., Veres K., Kakasy A.Z., Máthé I. Study of the oleanolic and ursolic acid contents of some species of the Lamiaceae. Biochem. Syst. Ecol. 2006;34:392-396.

    Not in our library10.1016/j.bse.2005.12.004

  37. 37.

    Caligiani A., Malavasi G., Palla G., Marseglia A., Tognolini M., Bruni R. A simple GC–MS method for the screening of betulinic, corosolic, maslinic, oleanolic and ursolic acid contents in commercial botanicals used as food supplement ingredients. Food Chem. 2013;136:735-741.

    Not in our library10.1016/j.foodchem.2012.08.011

  38. 38.

    Razboršek M.I., Vončina D.B., Doleček V., Vončina E. Determination of oleanolic, betulinic and ursolic acid in Lamiaceae and mass spectral fragmentation of their trimethylsilylated derivatives. Chromatographia. 2008;67:433-440.

    Not in our library10.1365/s10337-008-0533-6

  39. 39.

    Yin M.-C., Lin M.-C., Mong M.-C., Lin C.-Y. Bioavailability, distribution, and antioxidative effects of selected triterpenes in mice. J. Agric. Food Chem. 2012;60:7697-7701.

    Not in our library10.1021/jf302529x

  40. 40.

    Kanellos P.T., Kaliora A.C., Gioxari A., Christopoulou G.O., Kalogeropoulos N., Karathanos V.T. Absorption and bioavailability of antioxidant phytochemicals and increase of serum oxidation resistance in healthy subjects following supplementation with raisins. Plant Foods Hum. Nutr. 2013;68:411-415.

    Not in our library10.1007/s11130-013-0389-2

  41. 41.

    Zhao L., Li W., Li Y., Xu H., Lv L., Wang X., Chai Y., Zhang G. Simultaneous Determination of Oleanolic and Ursolic Acids in Rat Plasma by HPLC–MS: Application to a Pharmacokinetic Study After Oral Administration of Different Combinations of QingGanSanJie Decoction Extracts. J. Chromatogr. Sci. 2015;53:1185-1192.

    Not in our library10.1093/chromsci/bmu217

  42. 42.

    Jiang Q., Yang X., Du P., Zhang H., Zhang T. Dual strategies to improve oral bioavailability of oleanolic acid: Enhancing water-solubility, permeability and inhibiting cytochrome P450 isozymes. Eur. J. Pharm. Biopharm. 2016;99:65-72.

    Not in our library10.1016/j.ejpb.2015.11.013

  43. 43.

    Jeong D.W., Kim Y.H., Kim H.H., Ji H.Y., Yoo S.D., Choi W.R., Lee S.M., Han C., Lee H.S. Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats. Biopharm. Drug Dispos. 2007;28:51-57.

    Not in our library10.1002/bdd.530

  44. 44.
    Pentacyclic Triterpene Distribution in Various Plants – Rich Sources for a New Group of Multi-Potent Plant Extracts · 2009
    No notice
  45. 45.

    Li G.-L., You J.-M., Song C.-H., Xia L., Zheng J., Suo Y.-R. Development of a new HPLC method with precolumn fluorescent derivatization for rapid, selective and sensitive detection of triterpenic acids in fruits. J. Agric. Food Chem. 2011;59:2972-2979.

    Not in our library10.1021/jf104224t

  46. 46.

    Li X., Wang T., Zhou B., Gao W., Cao J., Huang L. Chemical composition and antioxidant and anti-inflammatory potential of peels and flesh from 10 different pear varieties (Pyrus spp.). Food Chem. 2014;152:531-538.

    Not in our library10.1016/j.foodchem.2013.12.010

  47. 47.

    Zhang S., Sun Y., Sun Z., Wang X., You J., Suo Y. Determination of triterpenic acids in fruits by a novel high performance liquid chromatography method with high sensitivity and specificity. Food Chem. 2014;146:264-269.

    Not in our library10.1016/j.foodchem.2013.09.056

  48. 48.

    Romero C., Medina E., Mateo M., Brenes M. Quantification of bioactive compounds in Picual and Arbequina olive leaves and fruit. J. Sci. Food Agric. 2016.

    Not in our library10.1002/jsfa.7920

  49. 49.

    Liese J., Abhari B.A., Fulda S. Smac mimetic and oleanolic acid synergize to induce cell death in human hepatocellular carcinoma cells. Cancer Lett. 2015;365:47-56.

    Not in our library10.1016/j.canlet.2015.04.018

  50. 50.

    Shi Y., Song Q., Hu D., Zhuang X., Yu S., Teng D. Oleanolic acid induced autophagic cell death in hepatocellular carcinoma cells via PI3K/Akt/mTOR and ROS-dependent pathway. Korean J. Physiol. Pharmacol. 2016;20:237-243.

    Not in our library10.4196/kjpp.2016.20.3.237

  51. 51.

    Shyu M.H., Kao T.C., Yen G.C. Oleanolic acid and ursolic acid induce apoptosis in HuH7 human hepatocellular carcinoma cells through a mitochondrial-dependent pathway and downregulation of XIAP. J. Agric. Food Chem. 2010;58:6110-6118.

    Not in our library10.1021/jf100574j

  52. 52.

    Wang X., Bai H., Zhang X., Liu J., Cao P., Liao N., Zhang W., Wang Z., Hai C. Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis. Carcinogenesis. 2013;34:1323-1330.

    Not in our library10.1093/carcin/bgt058

  53. 53.

    Lucio K.A., Rocha Gda G., Moncao-Ribeiro L.C., Fernandes J., Takiya C.M., Gattass C.R. Oleanolic acid initiates apoptosis in non-small cell lung cancer cell lines and reduces metastasis of a B16F10 melanoma model in vivo. PLoS ONE. 2011;6:e28596.

    Not in our library10.1371/journal.pone.0028596

  54. 54.

    Zhao X., Liu M., Li D. Oleanolic acid suppresses the proliferation of lung carcinoma cells by miR-122/Cyclin G1/MEF2D axis. Mol. Cell. Biochem. 2015;400:1-7.

    Not in our library10.1007/s11010-014-2228-7

  55. 55.

    Wu J., Yang C., Guo C., Li X., Yang N., Zhao L., Hang H., Liu S., Chu P., Sun Z., et al. SZC015, a synthetic oleanolic acid derivative, induces both apoptosis and autophagy in MCF-7 breast cancer cells. Chem. Biol. Interact. 2016;244:94-104.

    Not in our library10.1016/j.cbi.2015.11.013

  56. 56.

    Furtado R.A., Rodrigues E.P., Araujo F.R., Oliveira W.L., Furtado M.A., Castro M.B., Cunha W.R., Tavares D.C. Ursolic acid and oleanolic acid suppress preneoplastic lesions induced by 1,2-dimethylhydrazine in rat colon. Toxicol. Pathol. 2008;36:576-580.

    Not in our library10.1177/0192623308317423

  57. 57.

    Janakiram N.B., Indranie C., Malisetty S.V., Jagan P., Steele V.E., Rao C.V. Chemoprevention of colon carcinogenesis by oleanolic acid and its analog in male F344 rats and modulation of COX-2 and apoptosis in human colon HT-29 cancer cells. Pharm. Res. 2008;25:2151-2157.

    Not in our library10.1007/s11095-008-9582-7

  58. 58.

    Li L., Wei L., Shen A., Chu J., Lin J., Peng J. Oleanolic acid modulates multiple intracellular targets to inhibit colorectal cancer growth. Int. J. Oncol. 2015;47:2247-2254.

    Not in our library10.3892/ijo.2015.3198

  59. 59.

    Mu D.W., Guo H.Q., Zhou G.B., Li J.Y., Su B. Oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling. Int. J. Clin. Exp. Pathol. 2015;8:13864-13870.

    Not in our library

  60. 60.

    Li X., Song Y., Zhang P., Zhu H., Chen L., Xiao Y., Xing Y. Oleanolic acid inhibits cell survival and proliferation of prostate cancer cells in vitro and in vivo through the PI3K/Akt pathway. Tumour Biol. 2016;37:7599-7613.

    Not in our library10.1007/s13277-015-4655-9

  61. 61.

    Wei J., Liu H., Liu M., Wu N., Zhao J., Xiao L., Han L., Chu E., Lin X. Oleanolic acid potentiates the antitumor activity of 5-fluorouracil in pancreatic cancer cells. Oncol. Rep. 2012;28:1339-1345.

    Not in our library10.3892/or.2012.1921

  62. 62.

    Wei J., Liu M., Liu H., Wang H., Wang F., Zhang Y., Han L., Lin X. Oleanolic acid arrests cell cycle and induces apoptosis via ROS-mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells. J. Appl. Toxicol. 2013;33:756-765.

    Not in our library10.1002/jat.2725

  63. 63.

    Gao L., Xu Z., Wang Y., Sun B., Song Z., Yang B., Liu X., Lin Y., Peng J., Han G., et al. Anticancer effect of SZC017, a novel derivative of oleanolic acid, on human gastric cancer cells. Oncol. Rep. 2016;35:1101-1108.

    Not in our library10.3892/or.2015.4447

  64. 64.

    Li H.F., Wang X.A., Xiang S.S., Hu Y.P., Jiang L., Shu Y.J., Li M.L., Wu X.S., Zhang F., Ye Y.Y., et al. Oleanolic acid induces mitochondrial-dependent apoptosis and G0/G1 phase arrest in gallbladder cancer cells. Drug Des. Dev. Ther. 2015;9:3017-3030.

    Not in our library10.2147/dddt.s84448

  65. 65.

    Hua Y., Zhang Z., Li J., Li Q., Hu S., Li J., Sun M., Cai Z. Oleanolic acid derivative Dex-OA has potent anti-tumor and anti-metastatic activity on osteosarcoma cells in vitro and in vivo. Investig. New Drugs. 2011;29:258-265.

    Not in our library10.1007/s10637-009-9354-1

  66. 66.

    Zhang P., Li H., Chen D., Ni J., Kang Y., Wang S. Oleanolic acid induces apoptosis in human leukemia cells through caspase activation and poly(ADP-ribose) polymerase cleavage. Acta Biochim. Biophys. Sin. 2007;39:803-809.

    Not in our library10.1111/j.1745-7270.2007.00335.x

  67. 67.

    Fujiwara Y., Komohara Y., Kudo R., Tsurushima K., Ohnishi K., Ikeda T., Takeya M. Oleanolic acid inhibits macrophage differentiation into the M2 phenotype and glioblastoma cell proliferation by suppressing the activation of STAT3. Oncol. Rep. 2011;26:1533-1537.

    Not in our library10.3892/or.2011.1454

  68. 68.

    Guo G., Yao W., Zhang Q., Bo Y. Oleanolic acid suppresses migration and invasion of malignant glioma cells by inactivating MAPK/ERK signaling pathway. PLoS ONE. 2013;8:e72079.

    Not in our library10.1371/journal.pone.0072079

  69. 69.

    Tokuda H., Ohigashi H., Koshimizu K., Ito Y. Inhibitory effects of ursolic and oleanolic acid on skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Lett. 1986;33:279-285.

    Not in our library10.1016/0304-3835(86)90067-4

  70. 70.

    Oguro T., Liu J., Klaassen C.D., Yoshida T. Inhibitory effect of oleanolic acid on 12-O-tetradecanoylphorbol-13-acetate-induced gene expression in mouse skin. Toxicol. Sci. 1998;45:88-93.

    Not in our library10.1006/toxs.1998.2485

  71. 71.

    Zhu Y.Y., Huang H.Y., Wu Y.L. Anticancer and apoptotic activities of oleanolic acid are mediated through cell cycle arrest and disruption of mitochondrial membrane potential in HepG2 human hepatocellular carcinoma cells. Mol. Med. Rep. 2015;12:5012-5018.

    Not in our library10.3892/mmr.2015.4033

  72. 72.

    Thomas M., Deiters A. MicroRNA miR-122 as a therapeutic target for oligonucleotides and small molecules. Curr. Med. Chem. 2013;20:3629-3640.

    Not in our library10.2174/0929867311320290009

  73. 73.

    Nie H., Wang Y., Qin Y., Gong X.G. Oleanolic acid induces autophagic death in human gastric cancer cells in vitro and in vivo. Cell Biol. Int. 2016;40:770-778.

    Not in our library10.1002/cbin.10612

  74. 74.

    Liu J., Zheng L., Wu N., Ma L., Zhong J., Liu G., Lin X. Oleanolic acid induces metabolic adaptation in cancer cells by activating the AMP-activated protein kinase pathway. J. Agric. Food. Chem. 2014;62:5528-5537.

    Not in our library10.1021/jf500622p

  75. 75.

    Liu J., Ma L., Chen X., Wang J., Yu T., Gong Y., Ma A., Zheng L., Liang H. ERK inhibition sensitizes cancer cells to oleanolic acid-induced apoptosis through ERK/Nrf2/ROS pathway. Tumour Biol. 2016;37:8181-8187.

    Not in our library10.1007/s13277-015-4668-4

  76. 76.

    Yoshimura H., Sugawara K., Saito M., Saito S., Murakami S., Miyata N., Kawashima A., Morimoto S., Gao N., Zhang X., et al. In vitro TGF-β1 antagonistic activity of ursolic and oleanolic acids isolated from Clerodendranthus spicatus. Planta Med. 2003;69:673-675.

    Not in our library10.1055/s-2003-41110

  77. 77.

    Akhurst R.J., Hata A. Targeting the TGF β signalling pathway in disease. Nat. Rev. Drug Discov. 2012;11:790-811.

    Not in our library10.1038/nrd3810

  78. 78.

    Murakami S., Takashima H., Sato-Watanabe M., Chonan S., Yamamoto K., Saitoh M., Saito S., Yoshimura H., Sugawara K., Yang J., et al. Ursolic acid, an antagonist for transforming growth factor (TGF)-β1. FEBS Lett. 2004;566:55-59.

    Not in our library10.1016/j.febslet.2004.04.036

  79. 79.

    Lagadec P., Griessinger E., Nawrot M.P., Fenouille N., Colosetti P., Imbert V., Mari M., Hofman P., Czerucka D., Rousseau D., et al. Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells. Br. J. Cancer. 2008;98:335-344.

    Not in our library10.1038/sj.bjc.6604082

  80. 80.

    Chung T.W., Choi H., Lee J.M., Ha S.H., Kwak C.H., Abekura F., Park J.Y., Chang Y.C., Ha K.T., Cho S.H., et al. Oldenlandia diffusa suppresses metastatic potential through inhibiting matrix metalloproteinase-9 and intercellular adhesion molecule-1 expression via p38 and ERK1/2 MAPK pathways and induces apoptosis in human breast cancer MCF-7 cells. J. Ethnopharmacol. 2017;195:309-317.

    Not in our library10.1016/j.jep.2016.11.036

  81. 81.

    Willimott S., Barker J., Jones L.A., Opara E.I. Apoptotic effect of Oldenlandia diffusa on the leukaemic cell line HL60 and human lymphocytes. J. Ethnopharmacol. 2007;114:290-299.

    Not in our library10.1016/j.jep.2007.08.030

  82. 82.

    Sadava D., Ahn J., Zhan M., Pang M.L., Ding J., Kane S.E. Effects of four Chinese herbal extracts on drug-sensitive and multidrug-resistant small-cell lung carcinoma cells. Cancer Chemother. Pharmacol. 2002;49:261-266.

    Not in our library10.1007/s00280-002-0427-5

  83. 83.

    Wen L., Guo R., You L., Abbasi A.M., Li T., Fu X., Liu R.H. Major triterpenoids in Chinese hawthorn “Crataegus pinnatifida” and their effects on cell proliferation and apoptosis induction in MDA-MB-231 cancer cells. Food Chem. Toxicol. 2017;100:149-160.

    Not in our library10.1016/j.fct.2016.12.032

  84. 84.

    Mishra T., Arya R.K., Meena S., Joshi P., Pal M., Meena B., Upreti D.K., Rana T.S., Datta D. Isolation, Characterization and Anticancer Potential of Cytotoxic Triterpenes from Betula utilis Bark. PLoS ONE. 2016;11:e0159430.

    Not in our library10.1371/journal.pone.0159430

  85. 85.

    Konopleva M., Tsao T., Estrov Z., Lee R.M., Wang R.Y., Jackson C.E., McQueen T., Monaco G., Munsell M. The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia. Cancer Res. 2004;64:7927-7935.

    Not in our library10.1158/0008-5472.can-03-2402

  86. 86.

    Chakravarti B., Maurya R., Siddiqui J.A., Bid H.K., Rajendran S.M., Yadav P.P., Konwar R. In vitro anti-breast cancer activity of ethanolic extract of Wrightia tomentosa: Role of pro-apoptotic effects of oleanolic acid and urosolic acid. J. Ethnopharmacol. 2012;142:72-79.

    Not in our library10.1016/j.jep.2012.04.015

  87. 87.

    Rui L.X., Shu S.Y., Jun W.J., Mo C.Z., Wu S.Z., Min L.S., Yuan L., Yong P.J., Cheng S.Z., Sheng W.S., et al. The dual induction of apoptosis and autophagy by SZC014, a synthetic oleanolic acid derivative, in gastric cancer cells via NF-κB pathway. Tumour Biol. 2016;37:5133-5144.

    Not in our library10.1007/s13277-015-4293-2

  88. 88.

    Zou W., Liu X., Yue P., Zhou Z., Sporn M.B., Lotan R., Khuri F.R., Sun S.Y. c-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells. Cancer Res. 2004;64:7570-7578.

    Not in our library10.1158/0008-5472.can-04-1238

  89. 89.

    Lange M., Abhari B.A., Hinrichs T.M., Fulda S., Liese J. Identification of a novel oxidative stress induced cell death by Sorafenib and oleanolic acid in human hepatocellular carcinoma cells. Biochem. Pharmacol. 2016;118:9-17.

    Not in our library10.1016/j.bcp.2016.08.011

  90. 90.

    Liu J., Wu N., Ma L.N., Zhong J.T., Liu G., Zheng L.H., Lin X.K. p38 MAPK signaling mediates mitochondrial apoptosis in cancer cells induced by oleanolic acid. Asian Pac. J. Cancer Prev. 2014;15:4519-4525.

    Not in our library10.7314/apjcp.2014.15.11.4519

  91. 91.

    Amara S., Zheng M., Tiriveedhi V. Oleanolic Acid Inhibits High Salt-Induced Exaggeration of Warburg-like Metabolism in Breast Cancer Cells. Cell Biochem. Biophys. 2016;74:427-434.

    Not in our library10.1007/s12013-016-0736-7

  92. 92.

    Liu J., Wu N., Ma L., Liu M., Liu G., Zhang Y., Lin X. Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms. PLoS ONE. 2014;9:e91606.

    Not in our library10.1371/journal.pone.0091606

  93. 93.

    Walczak H., Bouchon A., Stahl H., Krammer P.H. Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2-or Bcl-xL-overexpressing chemotherapy-resistant tumor cells. Cancer Res. 2000;60:3051-3057.

    Not in our library

  94. 94.

    Pan G., Ni J., Wei Y.F., Yu G.L., Gentz R., Dixit V.M. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 1997;277:815-818.

    Not in our library10.1126/science.277.5327.815

  95. 95.
    Getting TRAIL back on track for cancer therapy · 2014
    No notice
  96. 96.

    Koornstra J.J., Kleibeuker J.H., van Geelen C.M., Rijcken F.E., Hollema H., de Vries E.G., de Jong S. Expression of TRAIL (TNF-related apoptosis-inducing ligand) and its receptors in normal colonic mucosa, adenomas, and carcinomas. J. Pathol. 2003;200:327-335.

    Not in our library10.1002/path.1364

  97. 97.

    Twomey J.D., Kim S.R., Zhao L., Bozza W.P., Zhang B. Spatial dynamics of TRAIL death receptors in cancer cells. Drug Resist. Updat. 2015;19:13-21.

    Not in our library10.1016/j.drup.2015.02.001

  98. 98.

    Boatright K.M., Salvesen G.S. Mechanisms of caspase activation. Curr. Opin. Cell Biol. 2003;15:725-731.

    Not in our library10.1016/j.ceb.2003.10.009

  99. 99.

    Salvesen G.S., Dixit V.M. Caspases: Intracellular signaling by proteolysis. Cell. 1997;91:443-446.

    Not in our library10.1016/s0092-8674(00)80430-4

  100. 100.

    Kominami K., Nakabayashi J., Nagai T., Tsujimura Y., Chiba K., Kimura H., Miyawaki A., Sawasaki T., Yokota H., Manabe N., et al. The molecular mechanism of apoptosis upon caspase-8 activation: Quantitative experimental validation of a mathematical model. Biochim. Biophys. Acta (BBA) Mol. Cell Res. 2012;1823:1825-1840.

    Not in our library10.1016/j.bbamcr.2012.07.003

  101. 101.

    Kantari C., Walczak H. Caspase-8 and bid: Caught in the act between death receptors and mitochondria. Biochim. Biophys. Acta (BBA) Mol. Cell Res. 2011;1813:558-563.

    Not in our library10.1016/j.bbamcr.2011.01.026

  102. 102.

    Jiang X., Wang X. Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J. Biol. Chem. 2000;275:31199-31203.

    Not in our library10.1074/jbc.c000405200

  103. 103.

    Jelínek M., Balušíková K., Schmiedlová M., Němcová-Fürstová V., Šrámek J., Stančíková J., Zanardi I., Ojima I., Kovář J. The role of individual caspases in cell death induction by taxanes in breast cancer cells. Cancer Cell Int. 2015;15:8.

    Not in our library10.1186/s12935-015-0155-7

  104. 104.

    Yoo K.H., Park J.H., Cui E.J., Kim K.I., Kim J.Y., Kim J., Hong S.G., Baek N.I., Chung I.S. 3-O-acetyloleanolic acid induces apoptosis in human colon carcinoma HCT-116 cells. Phytother. Res. 2012;26:1541-1546.

    Not in our library10.1002/ptr.4616

  105. 105.

    Ravanan P., Sano R., Talwar P., Ogasawara S., Matsuzawa S., Cuddy M., Singh S.K., Rao G.S., Kondaiah P., Reed J.C. Synthetic triterpenoidcyanoenone of methyl boswellate activates intrinsic, extrinsic, and endoplasmic reticulum stress cell death pathways in tumor cell lines. Mol. Cancer Ther. 2011;10:1635-1643.

    Not in our library10.1158/1535-7163.mct-10-0887

  106. 106.

    Zou W., Yue P., Khuri F.R., Sun S.Y. Coupling of endoplasmic reticulum stress to CDDO-Me-induced up-regulation of death receptor 5 via a CHOP-dependent mechanism involving JNK activation. Cancer Res. 2008;68:7484-7492.

    Not in our library10.1158/0008-5472.can-08-1318

  107. 107.

    Riccioni R., Senese M., Diverio D., Riti V., Mariani G., Boe A., LoCoco F., Foà R., Peschle C., Sporn M., et al. Resistance of acute myeloid leukemic cells to the triterpenoid CDDO-Imidazolide is associated with low caspase-8 and FADD levels. Leuk. Res. 2008;32:1244-1258.

    Not in our library10.1016/j.leukres.2007.12.008

  108. 108.

    Li L., Lin J., Sun G., Wei L., Shen A., Zhang M., Peng J. Oleanolic acid inhibits colorectal cancer angiogenesis in vivo and in vitro via suppression of STAT3 and Hedgehog pathways. Mol. Med. Rep. 2016;13:5276-5282.

    Not in our library10.3892/mmr.2016.5171

  109. 109.

    Elsayed H.E., Akl M.R., Ebrahim H.Y., Sallam A.A., Haggag E.G., Kamal A.M., El Sayed K.A. Discovery, optimization, and pharmacophore modeling of oleanolic acid and analogues as breast cancer cell migration and invasion inhibitors through targeting BRK/Paxillin/Rac1 axis. Chem. Biol. Drug Des. 2015;85:231-243.

    Not in our library10.1111/cbdd.12380

  110. 110.

    Shan J.Z., Xuan Y.Y., Ruan S.Q., Sun M. Proliferation-inhibiting and apoptosis-inducing effects of ursolic acid and oleanolic acid on multi-drug resistance cancer cells in vitro. Chin. J. Integr. Med. 2011;17:607-611.

    Not in our library10.1007/s11655-011-0815-y

  111. 111.

    Braga F., Ayres-Saraiva D., Gattass C.R., Capella M.A. Oleanolic acid inhibits the activity of the multidrug resistance protein ABCC1 (MRP1) but not of the ABCB1 (P-glycoprotein): Possible use in cancer chemotherapy. Cancer Lett. 2007;248:147-152.

    Not in our library10.1016/j.canlet.2006.06.008

  112. 112.

    Fernandes J., Castilho R.O., da Costa M.R., Wagner-Souza K., Coelho Kaplan M.A., Gattass C.R. Pentacyclictriterpenes from Chrysobalanaceae species: Cytotoxicity on multidrug resistant and sensitive leukemia cell lines. Cancer Lett. 2003;190:165-169.

    Not in our library10.1016/s0304-3835(02)00593-1

  113. 113.

    Wang J., Yu M., Xiao L., Xu S., Yi Q., Jin W. Radiosensitizing effect of oleanolic acid on tumor cells through the inhibition of GSH synthesis in vitro. Oncol. Rep. 2013;30:917-924.

    Not in our library10.3892/or.2013.2510

  114. 114.

    Bednarczyk-Cwynar B., Ruszkowski P., Bobkiewicz-Kozlowska T., Zaprutko L. Oleanolic Acid A-lactams Inhibit the Growth of HeLa, KB, MCF-7 and Hep-G2 Cancer Cell Lines at Micromolar Concentrations. Anticancer Agents Med. Chem. 2016;16:579-592.

    Not in our library10.2174/1871520615666150907095756

  115. 115.

    Sommerwerk S., Heller L., Kuhfs J., Csuk R. Urea derivates of ursolic, oleanolic and maslinic acid induce apoptosis and are selective cytotoxic for several human tumor cell lines. Eur. J. Med. Chem. 2016;119:1-16.

    Not in our library10.1016/j.ejmech.2016.04.051

  116. 116.

    Ren Y., Liu Y., Yang Z., Niu R., Gao K., Yang B., Liao X., Zhang J. Solid inclusion complexes of oleanolic acid with amino-appended β-cyclodextrins (ACDs): Preparation, characterization, water solubility and anticancer activity. Mater. Sci. Eng. C Mater. Biol. Appl. 2016;69:68-76.

    Not in our library10.1016/j.msec.2016.05.022

  117. 117.

    Luo Y., Liu Z., Zhang X., Huang J., Yu X., Li J., Xiong D., Sun X., Zhong Z. Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo. Int. J. Nanomed. 2016;11:3111-3129.

    Not in our library10.2147/ijn.s108445

  118. 118.

    Man D.K., Casettari L., Cespi M., Bonacucina G., Palmieri G.F., Sze S.C., Leung G.P., Lam J.K., Kwok P.C. Oleanolic Acid Loaded PEGylated PLA and PLGA Nanoparticles with Enhanced Cytotoxic Activity against Cancer Cells. Mol. Pharm. 2015;12:2112-2125.

    Not in our library10.1021/acs.molpharmaceut.5b00085

Cited by papers we hold 2

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.